Key strategies to mitigate the risks of asthma drug development

Approximately 300 million people globally have asthma, resulting in around 1,000 deaths per day.¹  While the number of approved treatments has grown in the last decades, there is still an unmet need for effective therapies. Many patients suffer from poor asthma control because they are undiagnosed or undertreated. 

Triggers for asthma exacerbations include air pollution, allergies, stress, exercise, weather, smoke, infections, and chemical exposure. Symptoms can be non-specific and vary from coughing and wheezing to shortness of breath and chest tightness. A key feature of asthma is the high degree of variability in its presentation and severity. Patients with different asthma phenotypes, such as allergic, non-allergic, eosinophilic, neutrophilic, or exercise-induced, may respond differently to therapies based on their mechanism of action (MoA). Asthma severity varies by region and is based on multiple factors, including housing conditions, air pollution exposure, socioeconomic status, and local standards of care. As a result, clinical trials in asthma are uniquely challenging for sponsors and investigators. 

We reviewed the European Public Assessment Reports (EPARs) for asthma medicines authorized in the EU to identify critical factors in successful asthma drug development. We also conducted a literature review of the effects of COVID-19 on the prevalence of asthma exacerbations and whether the use of novel endpoints could benefit development.² 

At Parexel, we have helped support hundreds of asthma trials, from Phase 1 to post-marketing surveillance. Based on our operational expertise and analyses of published data, we recommend five strategies to mitigate key risks in asthma drug development: 

1. Optimize patients’ inhaler technique and compliance

There are wide variations globally in asthma management regimens and patient compliance. A 2017 analysis of 3,660 asthma patients linked specific inhaler errors—such as weak air intake and actuating the device before inhaling—to a higher rate of exacerbations and uncontrolled disease.³  A recent systematic review showed that patients who used their inhalers correctly had better asthma outcomes.⁴  

Differences in patients’ adherence to background therapy and inhaler technique can impact the anticipated efficacy of an investigational product, which has consequences for trial design in terms of power and sample size calculations. 

We advise sponsors to design trials with an adequate run-in period to assess patients’ inhaler technique, background care compliance, and background medication stability. Patient education and monitoring are essential for correct administration and compliance throughout a clinical trial.

Leveraging patient insights gained from surveys, in-depth interviews, and focus groups is a proven way to design trials that make it easier for patients to practice optimal inhaler techniques, comply with treatment protocols, and stay engaged in studies. 

Recently, a sponsor asked Parexel to analyze the feasibility of their clinical trial for children and adolescents with severe eosinophilic asthma. After consulting patients and their parents, we recommended changing the draft protocol to add patient retention strategies such as gamification and video explanations and allow flexible timing for assessment visits (including telehealth visits) when feasible. The patient-guided changes to the trial’s design improved protocol compliance.

2. Choose trial sites strategically

Selecting investigative sites is critical to the success of any study, and it requires a significant investment in planning. Asthma trials typically target patients with a specific phenotype based on the investigational medicine’s MoA and simultaneously seek to enroll diverse patients in terms of disease severity, gender, age, ethnicity, and socioeconomic status. When choosing sites, sponsors must account for regional differences in medical practice and the availability of other effective therapies, such as biological agents (for example, some biologics are not reimbursed or widely accessible in certain regions).

Although the FDA and EMA have published regulatory guidelines for asthma drug development, they do not detail how sponsors can account for complex site selection or environmental considerations. For example, evidence suggests that particle pollution—from traffic, nitrogen dioxide, and second-hand smoke—worsens asthma outcomes and is a significant risk factor for children.⁵  Thus, sponsors might want to consider how ambient air pollution could impact asthma management during a trial and for pivotal trials that enroll patients from diverse regions and backgrounds.

At Parexel, we advise sponsors to consider protocol eligibility criteria, regional variations, and background therapy when selecting trial sites. To avoid bias, choose sites that can enroll a representative sample of the intended treatment population and randomize patients by key stratification factors. Meticulous and data-driven site selection ensures that trial results are valid, meet regulatory expectations, and are generalizable to patients in the real world.

3. Consider composite efficacy endpoints

The frequency of asthma exacerbations is a critical metric used to stratify patients for clinical trials and gauge the efficacy of new agents. Measures enacted to reduce the spread of COVID-19 in 2020, such as face masks, social distancing, quarantines, and school closures, also reduced exacerbations of chronic respiratory diseases, including asthma.⁶  For various reasons—including lower post-pandemic exposure to respiratory viruses such as rhinoviruses⁷ —the lower incidence rate of exacerbations has persisted after the pandemic ended. As a result, asthma trials targeting patients with high baseline rates of exacerbations now take longer to enroll, and more patients must be recruited to demonstrate a positive effect. 

Another traditional metric for evaluating asthma drugs in dose-finding and efficacy studies is the investigational medicine's effect on lung function. However, lack of compliance, faulty inhaler technique, inadequate training, and inconsistent quality in pulmonary function testing may compromise the integrity of lung function measurements as endpoints.

To avoid the pitfalls of single-factor endpoints, we advise sponsors to consider composite endpoints as primary, or at least secondary, endpoints to measure asthma exacerbations and symptom control in trials. A composite endpoint combines lung function parameters, exacerbation incidents, frequency of rescue inhaler use, and assessment of asthma control using validated questionnaires. One example is CompEx, a composite endpoint that demonstrated in a recent study it could enable shorter trials with fewer patients compared to studies that use severe exacerbations as the primary endpoint.⁷  Sponsors can use composite endpoints to capture clinically relevant deteriorations and effects, which could inform critical development decisions.

4. Utilize decentralized approaches when feasible

Decentralized clinical trials (DCTs) can boost patient enrollment in asthma trials by reducing participation burdens, such as time spent traveling to sites for data collection. A fully or partially (hybrid) decentralized study is optimal for some patients, while others may prefer traditional site visits. 

Recently, we helped a large pharma company optimize its protocol for a DCT in adolescent asthma patients. Due to their busy academic and activity schedules, adolescents are challenging to recruit into clinical trials. After vetting our trial design with potential participants, we learned that about two-thirds of asthma patients preferred home nursing visits, while one-third preferred site visits. We modified the protocol to include options for site-based blood sampling and let patients choose how they would participate. 

At Parexel, we have conducted more than 275 DCTs and, in partnership with sponsors, have tested end-to-end data collection using multiple mobile health sensors and devices in pilot studies.

For DCTs, capturing electronic data via mobile sensors requires patient compliance and reliable internet access. There must be no discrepancies in data recorded during a site visit or at home, especially if a trial occurs in both settings. One of our pilot studies that compared spirometer data collected at sites versus at home revealed a high degree of variability, compromising results. On closer examination, we found that the site staff who administered spirometry tests encouraged trial participants to attempt maximal force for each of the three required spirometry readings. In contrast, patients who took the test at home had no such encouragement.⁸ Differences like this can contribute to bias and lack of repeatability, so sponsors must ensure quality data collection. 

5. Engage with global regulators early

Regulatory agencies can make different decisions based on the same data. While some regulators may be more flexible in therapeutic areas with high unmet needs, others may not. Divergent decisions on product approval, indications, and mandatory post-marketing efficacy or safety studies can hamper a product’s market launch. Engaging with regulators early in development is the surest way for sponsors to anticipate regulatory, reimbursement, and commercial obstacles and design better trials to meet data needs. 
We advise sponsors to craft a global regulatory strategy, even if they initially intend to launch a product in one country or region. Agencies worldwide have developed expedited programs to speed the development of drugs for diseases with unmet needs. For example, the Priority Medicines (PRIME) scheme in the EU, Breakthrough Therapy Designation (BTD) in the U.S., and Sakigake designation in Japan can provide quicker access to these markets. Sometimes, joint meetings can be held with the FDA and the EMA. Sponsors can also leverage Access Consortium, which encompasses Australia, Canada, Singapore, Switzerland, and the United Kingdom, for faster approval in these countries.

The complexities of asthma require innovative approaches to drug development. By optimizing inhaler technique and strategically choosing trial sites, leveraging decentralized approaches, and engaging with regulators, sponsors can overcome challenges and accelerate the delivery of effective treatments to patients in need.

Partner with Parexel

With a team of over 1,300 regulatory professionals, , Parexel has the knowledge, insights, and technology-enabled processes to accelerate and streamline your drug development journey. Our experience in more than 110 countries allows us to provide strategic regulatory advice, proactively identify and mitigate risks, and navigate the ever-evolving regulatory landscape.

Our deep therapeutic insight and proven track record make us a reliable partner for achieving regulatory success. By engaging with us early, we can shape the plan and craft the best strategy for global engagement with regulators. We develop proof-of-concept protocols that support decision-making for pivotal studies and design streamlined patient-guided development.

We collaborate with subject matter experts to devise flexible and efficient strategies, ensuring that protocol assessments are manageable for patients. When feasible, we combine healthy volunteers and patients in one study to streamline the process. Our commitment to innovation and operational excellence helps us deliver life-saving treatments to patients more efficiently and effectively.

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Resources

1. Global Strategy for Asthma Management and Prevention (2024 Update), Global Initiative for Asthma (May 2024).
2. Managing risks: successful clinical development in asthma, Regulatory Rapporteur (March 3, 2024).
3. Inhaler Errors in the CRITIKAL Study: Type, Frequency, and Association with Asthma Outcomes, The Journal of Allergy and Clinical Immunology: In Practice (March 9, 2017). 
4. The impact of inhaler technique on clinical outcomes in adolescents and adults with asthma, Respiratory Medicine (September 2, 2022).
5. Impact of Air Pollution on Asthma Outcomes, International Journal of Environmental Research and Public Health (August 27, 2020). 
6. Asthma exacerbations during the pandemic: Time to rethink clinical markers, Journal of Allergy and Clinical Immunology: Global (October 20, 2022).
7. A novel endpoint for exacerbations in asthma to accelerate clinical development: a post-hoc analysis of randomized controlled trials, The Lancet Respiratory Medicine (July 2017).
8. A Pilot Study to Assess the Feasibility of Collecting and Transmitting Clinical Trial Data with Mobile Technologies, Digital Biomarkers (November 7, 2018).

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